Live attenuated or inactivated bacteria and viruses have formed the basis of many successful vaccines. The whole virus or bacteria approach remains the most effective means of generating protective immunity by vaccination. However, these vaccines can be associated with mild to severe side effects. Furthermore, rare cases of vaccine-associated disease can result from reversion of an attenuated virus to the virulent form. Advances in genomics, molecular biology and immunology have facilitated the identification, recombinant expression and immunological characterization of protective antigens from infectious organisms, permitting a more rational approach to vaccine design. Purified native or recombinant peptides, proteins or polysaccharides (linked to carrier proteins) now provide a much cleaner, safer and more immunologically defined alternative to live or killed whole cell vaccines. However, these “purer” vaccine preparations lack the danger signals required to activate innate immune responses and must therefore be delivered with potent adjuvants or delivery systems in order to generate protective adaptive immune responses.
Vaccine adjuvants can be used for multiple purposes, such as for example to increase efficacy, reduce the amount of antigen and/or number of doses required, enhance the rapidity and/or intensity of response, increase the breadth of response (e.g. to protect against multiple epitopes, such as might arise from pathogen evolution), and to enhance the duration of response and/or ability to prime for later response (memory). For example, recent increased interest in adjuvants concerns their use in cases of poor immunogens (such as pandemic influenza vaccine H5N1), insufficient manufacturing capacity (dose sparing) and broader specific immune response (mutating viruses). Adjuvants are also potentially important for vaccination of the elderly (who may be subject to immunoscenescence mechanisms), children (with low pre-existing immunity), and immunocompromised individuals with low capacity to respond to vaccination.
There are certain challenges associated with the use of adjuvants to stimulate the immune system in combination with the administration of a vaccine. Primarily, there is the importance of co-delivering and maintaining the antigen component and the immunostimulant component of the vaccine at the injection site, at least until contacting an immune cell. This is important to maximise the benefit of the adjuvant, but can also be necessary to reduce toxicity. Immunostimulants, such as agonists of Toll-like receptors (TLRs) or Nod-like receptors (NLRs), are typically small molecules which are readily transported throughout the body. They can therefore give rise to unacceptable clinical side effects due to systemic reactions, such as the triggering of autoimmune diseases.
It is known to covalently link an immunostimulant to a desired antigen, in order to ensure that both the antigen and the immunostimulant can be presented together to an immune cell. For example, WO 2012/167088 describes an “immune response modifier” covalently linked to an antigen by means of a linker comprising polyethylene glycol. WO 2004/032829 describes an immunostimulatory composition comprising an immune response modifier portion ‘paired with’ an antigenic portion, where the pairing may be by means of covalent linkage. WO 2006/116475 describes an immune response modifier covalently linked to an antigenic peptide.
It is also known to modify the chemical structure of an immunostimulant to aid in delivery. For example, WO 2012/024284 and WO 2010/048520 describe immunostimulants covalently linked to lipids, either to enable formulation or to improve bioavailability.